1. The Field of the Invention
The present invention is related to modalities for the mammalian administration of medicaments.
2. The Relevant Technology
Devices for delivering beneficial agents into the mouth of humans or animals have been sought after since recorded history. There are many medical conditions that would benefit from a device that would deliver a medication into the buccal cavity over an extended period of time. There are many devices that have been utilized from time to time with varying degrees of success. Most of these devices fall into the following categories: 1) Osmosis controlled devices, 2) Erosion controlled devices, 3) Diffusion controlled devices, 4) pH controlled devices, 5) Shrink polymer controlled devices, and 6) Pump controlled devices. Each method has its'merits and each method has its'shortcomings.
Recently, numerous advancements have taken place in the field of pharmacology and pharmaceutics with respect to the administration of drugs to treat various conditions. Despite the tremendous advancements in the field, however, drugs continue to be administered using substantially the same techniques that have been used for many decades. The vast majority of pharmaceutical agents continue to be administered either orally or by injection. Nevertheless, it is frequently found in the art that neither of these administration routes are effective in all cases, and both administration routes suffer from several disadvantages.
Oral administration is probably the most prevalent method of administering pharmacological medicaments. The medicament is generally incorporated into a tablet, capsule, or a liquid base, and then swallowed. The oral administration modality is often preferred because of its convenience. In addition, oral administration is Generally non-threatening, painless and simple to accomplish for most patients.
Nevertheless, oral administration of drugs suffers from several disadvantages. One disadvantage is that pediatric and geriatric patients frequently have difficulty swallowing pills and other solid dosage forms, and such patients often refuse to cooperate in swallowing liquid medication. In addition, for many medicaments, the act of swallowing the medicament often requires fluids that increase gastric volume and the likelihood of nausea and vomiting is also increased.
A further problem with oral administration is that the amount of the drug that gets into the bloodstream after swallowing varies from patient to patient. The absorption of the drug is dependent upon the movement of the drug from the stomach to the small and large intestines; the effects of secretions from these organs and the resulting pH within the stomach and intestines also influence the absorption. Anxiety and stress can dramatically reduce these movements and secretions preventing or reducing the final effects of the drug, and may delay the onset of the drug's effects.
Most significant is the fact that there is normally substantial delay between the time of oral administration and the time that the therapeutic effect of the drug begins. As mentioned above, the drug must pass through the gastrointestinal system in order to enter the bloodstream; this typically takes forty-five minutes or longer. As mentioned above, anxiety and stress often increase this delay.
For many applications, such as premedication before surgery or where immediate relief from pain or a serious medical condition or immediate effectiveness of the drug is required, this delay is unacceptable. In modern outpatient units and operating rooms where rapid turnover of patients is essential for cost containment, extensive delays in the action of a drug are simply unacceptable.
An additional disadvantage of oral administration is that many drugs almost immediately experience metabolism or inactivation. The veins from the stomach and the small and large intestines pass directly through the liver. Thus, drugs entering the bloodstream must first pass through the liver before distribution into the general blood circulation. More than sixty percent of most drugs (and essentially one hundred percent of certain drugs) are removed from the patient's bloodstream during this "first pass" through the liver. The result is that oral administration is impractical for many drugs, particularly many central nervous system and many cardiovascular-acting drugs that are used for rapid onset in critical care situations, as a premedication prior to surgery, or for the induction of anesthesia.
Further, additional stress is placed on the liver as it removes the excess drug from the bloodstream. This is particularly severe if the drug treatment has been occurring over an extended period of time. The liver may become overloaded with the drugs'metabolites which then must be excreted. As a result, there is an increased risk of hepatic or renal disorders.
Another difficulty encountered in administering drugs orally is that dosages are prepared or determined for use with an "average" patient. Most drugs have widely varying effects on different patients. These effects depend upon patient habits, subtle genetic differences between patients, blood volumes, age, and numerous other known and unknown factors. Introducing a drug orally does not provide the ability to control the precise dose needed to obtain the desired effect, rather the dose is estimated in order to produce an average effect in an average patient. The result may be underdosing or overdosing a particular patient.
Underdosing a patient because of a low susceptibility to the drug fails to evoke the response sought by the physician. Overdosing the patient can result in dangerous depression of vital body functions, especially the heart and lungs. This can cause prolonged respiratory depression (necessitating mechanical ventilation after surgery), cardiac depression, and arrest.
In order to avoid some of the disadvantages of oral administration, injection is frequently used, Injecting a drug (generally intravenously or intramuscularly), results in rapid entry of the drug into the patient's bloodstream. In addition, this type of delivery avoids the removal of large quantities of the drug by the patient's liver. As a result, less total drug is usually needed compared to orally administered drugs. The drug instead becomes rapidly distributed to various portions of the patient's body before exposure to the liver.
Most patients, particularly children and geriatric adults have an aversion to injections. In some patients, this aversion may be so pronounced as to make the use of injections a serious concern. Since intense psychological stress can exacerbate a patient's debilitated condition, it sometimes becomes undesirable to use injections where the patient is seriously ill or suffers from a debilitating condition or injury.
In addition, individual variations in susceptibility in the metabolism of various drugs (particularly drugs with central nervous system activity) are even more profound when utilizing the injection route. In many instances to prevent overdosing, it is the practice to inject a patient with a lower than average dose and then supplement the dose with additional injections as necessary. This "titration" makes necessary the use of repeated injections, which in turn greatly increases stress on the patient. Again, a precise dose cannot be administered to produce a precise effect because the patient's response varies widely depending on the specific characteristics of the patient.
One common approach to preparing a patient for surgery is to orally administer a sedative or an antianxiety drug. Although quick onset of sedation or anxiolysis has not always been a critical factor, it is more so now. Changing practices, including the increased use of outpatient units for day surgery and the pressures for cost containment in modern medicine, dictate rapid onset of action and the use of an absolutely ideal dose in order to avoid increased costs of caring for patients with delayed recovery secondary to slightly overdosing with anesthesia. Effective oral administration of premedication drugs with central nervous system activity (which cause a rapid onset of sedation and anxiolysis without producing excessive sedation) is often difficult to accomplish.
Some investigators have suggested that it may be possible to administer medication through the buccal mucosa of the check pouch or by sublingual administration. See, U.S. Pat. No. 4,671,953 entitled "METHODS AND COMPOSITIONS FOR NONINVASIVE ADMINISTRATION OF SEDATIVES, ANALGESICS, AND ANESTHETICS." Such administration through the mucosal tissues of the mouth, pharynx, and esophagus of therapeutic drugs possesses a distinct usefulness. Administration of drugs by this route does not expose the drug to the gastric and digestive juices. In addition the drugs largely bypass the liver on the first pass through the body, thereby avoiding additional metabolism and/or inactivation of the drug.
Generally the drugs which are administered by any of the methods described above have an unpleasant taste. As a result, in order to allow for buccal or sublingual administration through the oral mucosal tissues, it is also necessary to incorporate the drug into some type of pleasant tasting agent. While the administration of certain drugs through the oral mucosal tissues has shown promise, development of a fully acceptable method for producing a medication in a desirable form and administering the medication has been elusive. It has not been possible to develop an acceptable candy product for use with most drugs without heating the product to the point where degradation will be expected.
It should also be noted that pH conditions within the mouth may tend to adversely affect the effectiveness of certain drugs. It has been found in the art that administration of drugs through the mucosal tissues generally occurs best when the drug is in the unionized form; the unionized portion of the drug is usually lipid soluble (lipophilic) and can readily diffuse through the cell membrane. The ionized portion of the drug, conversely, is often lipid insoluble (nonlipophilic) and in most cases may not efficiently penetrate the lipid membrane of the cell. Drugs in the ionized form are generally inefficient in producing a drug effect on the central nervous system, the cardiovascular system or the renal vascular system. Variations in pH affect the percentage of the drug which is unionized at a particular point in time. As a result, the pH conditions within the mouth often limit the effectiveness of certain drugs administered buccally or sublingually in that those conditions cause the drug to exist in a form which is largely unavailable for transfer across the mucosal tissues.
Other potent drugs are substantially nonlipophilic and do not naturally permeate mucosal tissues. Hence it would be a significant advancement in the art of administering potent, fast acting drugs, if suitable methods and compositions permitted both lipophilic and nonlipophilic drugs to be administered transmucosally.
It would be another important advancement in the art of administering potent, fast-acting drugs, if suitable methods and compositions provided a precise dosage to a precise effect in every patient. A related advancement in the art would be to provide such methods and compositions that would avoid the disadvantages of overdosing, and the immediate metabolism encountered in the "first pass effect", yet do not involve injection by needle into the patient.
Many people suffer from a very serious medical condition called obesity. The definition of obesity is when an individual is 20% over that individuals normal weight. It is estimated that approximately 20% of the adult U.S. population suffers from obesity. World wide obesity approaches approximately 15%; the lower percentage is no doubt due to lower caloric laden foods in less affluent countries. The normal caloric intake for an adult man is approximately 2500 calories per day. The normal caloric intake for an adult woman is approximately 2000 calories per day. If the number of calories consumed over a 24 hour period of time equals the number of calories expended over a 24 hour period of time, an individuals'weight will stay the same. If the number of calories consumed over a 24 hour period of time is greater than the number of calories expended over a 24 hour period of time, an individuals'weight will increase as the excess calories are converted to fat and stored in the body. If the number of calories consumed over a 24 hour period of time is less than the number of calories expended, an individuals'weight will decrease as the deficit in calories consumed will cause fat stored in the body to be converted into calories to make up for the deficit in calorie intake. Thus, over a long period of time, excess caloric intake will cause an individual to become fat and possibly even obese. Also, over a long period of time, a deficit in calory intake will cause an individual to become thin as the body mobilizes and bums body fat to compensate for the deficit in caloric intake. Most nutritionists agree that three balanced, nutritious meals a day provide sufficient protein, carbohydrates, fat, vitamins and minerals for normal body function. Most individuals that suffer from an overweight condition or even from obesity have difficulty eating only three meals daily. These individuals have a tendency to eat between meals. This condition is called snacking and many of these snack foods are high calorie in content.
Thus, there is clearly a need for a device that will take away the desire to snack in between regular meals. This device would be a substitute for snack foods and offer a low or non-calorie alternative to high calorie snack foods. The device would also be designed to have a mode of action that would provide for a sustained or prolonged alternative to snack food.
There is clearly a need for a simple, economical device that will deliver a sustained release of beneficial agent into the oral cavity.